The genetic causes of salt sensitivity in humans are not well known. The kidney is critical to the overall fluid and electrolyte balance and long-term regulation of blood pressure (BP). Therefore, the pathogenesis of salt sensitivity must involve an inability to decrease sodium transport and increase sodium excretion when the sodium load is increased. Variants of the human G protein-coupled receptor kinase type 4 (hGRK) genes that regulates a limited number of G protein-coupled receptors, are associated with essential hypertension in several ethnic groups. Expression of the hGRK4g486V variant in mice causes salt sensitivity depending on the genetic background. Preliminary data suggest that the orphan receptor GPR83 may counteract the salt- sensitive producing effect of hGRK4g 486V, the expression of which is dependent on the genetic background and may explain ethnic-related differences in salt sensitivity. This project will test the overall novel hypothesis that salt sensitivity imparted by hGRK4g 486V is due to decreased expression/function of the orphan receptor GPR83 that results in an imbalance in natriuretic (dopamine D1 receptor, D1R) and antinatriuretic (angiotensin type 1 receptor, AT1R) systems which increases BP. Specific Aim 1 will test the hypothesis that GPR83 function is necessary to maintain a normal blood pressure under conditions of sodium excess and that lack or decreased GPR83 function will have the least effect on mice in a salt-resistant background. This Specific Aim 1 will also clarify the effects of GRK4 and D1R on the regulation of GPR83 expression. Specific Aim 2 will test the hypothesis that the protective effects of GPR83 are mediated by negative regulation of AT1R and positive regulation of D1R functions. This Specific Aim will clarify the cellular mechanisms involved in the regulation of these functions. Specific Aim 3 will test the hypothesis that GPR83 function is impaired by hGRK4g486V and that the ability to impair GPR83 function is dependent on the proportion of salt sensitivity and salt resistance genes. In mice with a predominant salt-sensitive background renal GPR83 is necessary to maintain normal blood pressure even when sodium intake is not increased. These studies will be able to determine, for the first time, the role of the interaction of salt sensitivity and salt resistance genes in the pathogenesis o essential hypertension. The identification of a novel salt resistance gene, i.e., GPR83, may lead to the development of drugs that target its expression and function.